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Decreased levels of keratin 8 sensitize mice to streptozotocin-induced diabetes

Alam, C.M.; Silvander, J.S.G.; Helenius, T.O.; Toivola, D.M.

Authors

J.S.G. Silvander

T.O. Helenius

D.M. Toivola



Abstract

Aim
Diabetes is a result of an interplay between genetic, environmental and lifestyle factors. Keratin intermediate filaments are stress proteins in epithelial cells, and keratin mutations predispose to several human diseases. However, the involvement of keratins in diabetes is not well known. K8 and its partner K18 are the main β-cell keratins, and knockout of K8 (K8−/−) in mice causes mislocalization of glucose transporter 2, mitochondrial defects, reduced insulin content and altered systemic glucose/insulin control. We hypothesize that K8/K18 offer protection during β-cell stress and that decreased K8 levels contribute to diabetes susceptibility.

Methods
K8-heterozygous knockout (K8+/−) and wild-type (K8+/+) mice were used to evaluate the influence of keratin levels on endocrine pancreatic function and diabetes development under basal conditions and after T1D streptozotocin (STZ)-induced β-cell stress and T2D high-fat diet (HFD).

Results
Murine K8+/− endocrine islets express ~50% less K8/K18 compared with K8+/+. The decreased keratin levels have little impact on basal systemic glucose/insulin regulation, β-cell health or insulin levels. Diabetes incidence and blood glucose levels are significantly higher in K8+/− mice after low-dose/chronic STZ treatment, and STZ causes more β-cell damage and polyuria in K8+/− compared with K8+/+. K8 appears upregulated 5 weeks after STZ treatment in K8+/+ islets but not in K8+/−. K8+/− mice showed no major susceptibility risk to HFD compared to K8+/+.

Conclusion
Partial K8 deficiency reduces β-cell stress tolerance and aggravates diabetes development in response to STZ, while there is no major susceptibility to HFD.

Journal Article Type Article
Acceptance Date Apr 23, 2018
Online Publication Date May 2, 2018
Publication Date 2018
Deposit Date May 13, 2022
Publicly Available Date Jun 27, 2023
Journal Acta physiologica
Print ISSN 1748-1708
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 224
Issue 2
Article Number e13085
DOI https://doi.org/10.1111/apha.13085
Keywords β-cell, cytoskeleton, diabetes, glucose-stimulated insulin secretion, high-fat diet, keratin intermediate filaments, streptozotocin
Public URL http://researchrepository.napier.ac.uk/Output/2869898
Publisher URL https://europepmc.org/articles/PMC6175344

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